1. The leaves of Mitragyna speciosa Korth. (Rubiaceae) have been traditionally used as a substitute for opium in Thai and Malaysia. Reinvestigation of the alkaloidal constituents of the plant in Malaysia resulted in the isolation of new 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids. The structures of the new compounds were elucidated by spectroscopic analysis and total synthesis.2. A potent opioid agonistic property of mitragynine, a major alkaloid of this plant, have been demonstrated. Based on this finding, more than 30 derivatives of mitragynine were prepared and their activity was evaluated in vitro. Among the compounds, mitragynine pseudoindoxyl and 7-hydroxymitragynine exhibited more potent affinity to (μ-) opioid receptor than that of morphine. Using those results, we investigated the structure-activity relationship to clarify the essential structural moieties for exhibiting the analgesic activity and then proposed a plausible binding model for the interaction mode between the opioid receptor and 7-hydroxymitragynine as a ligand.3. Further, we found that 7-hydroxymitragynine exhibited strong antinociceptive activity in vivo experiments (s.c. and p.o. administration) in mice, whose potency was far greater than that of morphine. This finding demonstrates that Mitragyna alkaloids or their derivatives could be the promissing lead-compound for the development of useful and practical analgesic agents.